Thymic adipogenesis and age-related thymic demise

描述（由申请人提供）：随着年龄的增长，胸腺产生幼稚T细胞的能力下降仍然是免疫学的一个基本和令人困惑的现象，迄今为止，这是一个难以解决的临床状况，导致老年人的免疫功能障碍。随着年龄的增长，胸腺经历了惊人的纤维化和脂肪变化，最终转变为脂肪组织。异位脂肪细胞的谱系和胸腺脂肪细胞在衰老过程中的发育机制尚不清楚。利用谱系追踪，我们的研究小组已经表明FoxN1+胸腺上皮细胞（TECs）， T细胞发育所必需的，可以转化和

DESCRIPTION (provided by applicant): Diminished ability of thymus to produce naive T cells with progressive aging remains a fundamental and puzzling phenomenon for immunology and to-date, an intractable clinical condition that contributes to immune dysfunction in elderly. With advancing age, the thymus undergoes striking fibrotic and fatty changes that culminate in its transformation into adipose tissue. The lineage of ectopic adipocytes and the mechanism of development of thymic adipocytes during aging are not well understood. Using lineage-tracing, our research team has shown that FoxN1+ thymic epithelial cells (TECs), that are necessary for T cell development, can transition and give rise to thymic adipogenic precursors. Consistent with this new paradigm, our lates preliminary data provide further in vivo evidence that proadipogenic cells in aging thymus can originate from epithelial and endothelial lineages via a secondary mesenchymal precursor. Based on our novel findings, the central hypothesis of this proposal is that the transition of TECs and endothelial cells contribute towards the lineage of thymic adipocytes and leads to age-related thymic involution. The corollary is that blocking the fibrogenesis and pro- adipogenic signaling in TEC and endothelial lineage cells will protect against aging of thymus. Experiments in Aim 1 will test the hypothesis 1 that with advancing age transition of FoxN1+ cells into adipogenic precursors via epithelial-mesenchymal transition (EMT) process gives rise to ectopic thymic adipocytes and compromises the thymic stromal microenvironment. Aim 2 will test the hypothesis 2 that that endothelial-lineage cells serve as adipogenic progenitors and will reveal that blocking he ectopic adipocyte development in thymic perivascular space protect against thymic aging. The Aim 3 will test the hypothesis 3 that age-related fibrogenesis in thymus causes reduction in thymopoiesis and reveal that mechanisms that commit secondary mesenchymal cells into adipocytes participate in thymic dysfunction. The long-term goal of this research project is to understand the mechanisms that cause thymic adiposity and to develop new approaches to prevent or reverse the process of age-related thymic involution.